Apolipoprotein (apo) E is a multifunctional protein that has central roles in lipid metabolism and neurobiology. It has three common isoforms (apoE2, apoE3 and apoE4) that have different effects on lipid and neuronal homneostasis. Unlike apoE3, tie most common isoform, apoE4 is a major risk factor for Alzheimer's disease (AD). Although the mechanisms underlying the actions of apoE4 in AD pathogenesis are still poorly understood, emerging data strongly suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to this disease by interacting with different factors through various pathways. Thus, multiple molecular and cellular mechanisms should be considered in developing anti-AD drugs that target apoE4.